Mendelian disorders causing hypertension

Article about Mendelian disorders causing hypertension - these are rare conditions. 

Essentials

Several mendelian disorders with hypertension as the predominant manifestation have been characterized at the molecular level. Features that may suggest one of these very rare conditions include a young age of onset, moderate to severe hypertension, strong family history, consanguinity (for the autosomal recessive disorders), and electrolyte abnormalities, particularly of potassium (although this is not invariable).

Glucocorticoid remediable aldosteronism—an autosomal dominant condition caused by a chimeric gene where the regulatory elements of the 11β-hydroxylase gene become attached to the coding region of aldosterone synthase. Hypertension responds to a low daily dose of exogenous glucocorticoid.

Apparent mineralocorticoid excess—an autosomal recessive disorder caused by mutations causing loss of function in the type 2 11β-hydroxysteroid dehydrogenase gene that normally inactivates cortisol in the kidney and prevents it binding to the mineralocorticoid receptor. The hypertension responds to spironolactone or amiloride.

Liddle’s syndrome—an autosomal dominant condition caused by activating mutations in genes encoding the β- or γ-subunits of the trimeric epithelial sodium channel. Hypertension responds to direct inhibitors triamterene or amiloride.

Pseudohypoaldosteronism type 2 (PHA2, Gordon’s syndrome)—an autosomal dominant condition, some cases of which are caused by mutations in serine-threonine kinases (WNK1 and WNK4) that regulate salt reabsorption by the Na-Cl cotransporter (SLC12A3) and the linked process of potassium secretion by the renal outer medullary potassium channel (ROMK). The hypertension and physiological abnormalities are corrected by thiazide diuretics.

Introduction

Several rare mendelian disorders where hypertension is the predominant manifestation have been characterized at the molecular level (Bullet list 1). These include glucocorticoid remediable aldosteronism, the syndrome of apparent mineralocorticoid excess, Liddle’s syndrome and Gordon’s syndrome. Hypertension and hypokalaemia are features of 11β-hydroxylase and 17β-hydroxylase deficiency—two rare recessive gene disorders of adrenal steroid-synthesizing enzymes that, among others, cause congenital adrenal hyperplasia. 11β-Hydroxylase deficiency usually presents in infancy or early childhood with virilization of both sexes, while presentation of 17β-hydroxylase deficiency may be delayed until adolesecence or adulthood. Hypertension due to a phaeochromocytoma may be a feature of multiple endocrine neoplasia type 2 (MEN2, Sipple’s syndrome), which when familial is inherited in an autosomal dominant pattern, or rarely to be a feature of neuro-fibromatosis (von Recklinghausen’s disease).

Bullet list1 Mendelian forms of blood pressure variation

Hypertension
  • Glucocoticoid-remediable aldosteronism (GRA)
  • Syndrome of apparent mineralocorticoid excess (AME)
  • Liddle’s syndrome
  • Gordon’s syndrome (pseudohypoaldosteronism type II, PHA-II)
  • Hypertension exacerbated by pregnancy
  • Hypertension with brachydactyly
  • 11β-Hydroxylase deficiency
  • 17β-Hydroxylase deficiency
  • Multiple endocrine neoplasia type 2 (Sipple’s syndrome) with phaeochromocytoma
Hypotension
  • Pseudohypoaldosteronism type 1
  • Gittleman’s syndrome
  • Bartter syndrome
  • 11β-hydroxylase deficiency
  • Aldosterone synthase deficiency

Glucocorticoid-remediable aldosteronism

Glucocorticoid-remediable aldosteronism (GRA) is a form of mineralocorticoid hypertension that is inherited in an autosomal dominant fashion. The hypertension is accompanied by hypokalaemia (not invariably), a tendency to metabolic alkalosis, an elevated plasma aldosterone level and a suppressed renin level, and it often responds to thiazides or spironolactone. Patients are usually suspected of having primary aldosteronism (Conn’s syndrome, see Chapter 16.17.4), although the age of onset, usually in the first two decades of life, is younger than typical of primary aldosteronism. Intracranial aneurysms are common and the first manifestation may be a presentation with intracranial haemorrhage.

The two hallmarks features of GRA are the presence of large amounts of two abnormal steroids—18-hydroxycortisol and 18-oxocortisol—in the urine, and the paradoxical response of the hypertension, with return of plasma aldosterone to a normal level and disappearance of the abnormal steroids, following treatment over a few days with a low daily dose of exogenous glucocorticoid, e.g. 0.5 to 1.0 mg of dexamethasone (hence the name).

Patients with GRA have a chimeric gene due to an unequal crossing-over event at meiosis between two adjacent and highly homologous genes involved in adrenocorticosteroid synthesis—aldosterone synthase (CYP11B2) (normally expressed only in the zona glomerulosa, involved in aldosterone synthesis and regulated by angiotensin II) and 11β-hydroxylase (CYP11B1) (expressed in the zona fasciculata, involved in glucocorticoid synthesis and regulated by ACTH). In the chimeric gene, the regulatory elements of CYP11B1 have become attached to the aldosterone synthase coding region of CYP11B2. This leads to ACTH-driven production of aldosterone (and the other abnormal hormones) in the zona fasciculata, hence the clinical syndrome and its suppression by glucocorticoids.

The mainstay of treatment for GRA is glucocorticoids, with physiological doses (or only slightly higher, e.g. 0.125 mg of dexamethasone or 2.5 mg of prednisolone daily) sufficing. Response can be monitored by measuring the suppression of aldosterone production. Selective mineralocorticoid receptor blockers, such as spironolactone, can provide useful adjunctive treatment.

Syndrome of apparent mineralocorticoid excess

The syndrome of apparent mineralocorticoid excess (AME) is an autosomal recessive disorder that usually presents in childhood with hypertension, hypokalaemia, and low renin activity. Despite the clinical features of mineralocorticoid excess, levels of all known mineralocorticoid hormones are low, yet the hypertension responds to spironolactone or amiloride. Patients with the disorder cannot metabolize cortisol to its inactive metabolite cortisone normally, resulting in a prolonged half-life of cortisol and a characteristic increase in urinary cortisol (compound F) compared with cortisone (compound E) ratio.

Elucidating the defect causing AME first required the solution of another paradox—why cortisol, which circulates at a level several-fold greater than aldosterone, does not overwhelmingly activate the renal mineralocorticoid receptor in vivo despite the two having equal affinity in vitro. The reason relates to the enzyme 11β-hydroxysteroid dehydrogenase (11β-HSD), which has two isoforms. Type 1 11β-HSD is located in the liver, adipose tissue and gonad and converts cortisone to cortisol. Type 2 11β-HSD is expressed in the mineralocorticoid target tissues—kidney, colon, and salivary gland—and inactivates cortisol to cortisone. In the kidney the enzyme plays the crucial role of protecting the mineralcorticoid receptor on the distal tubule from activation by cortisol. In subjects with AME a variety of loss-of-function mutations in the type 2 11β-HSD gene cause a deficiency of the enzyme, allowing cortisol access to the mineralocorticoid receptor.

The severe form of AME, due to disabling mutations in type 2 11β-HSD, usually presents in childhood. Recently a milder form, termed AME type II, has been described, which is characterized by a later age of presentation (>30 years), a more variable degree of hypertension, and less impact on biochemical parameters. These patients have alterations in 11β-HSD2 that produce a partial rather than absolute decrease in enzymatic activity. The mainstay of treatment of either form of AME is spironolactone. A low-salt diet is also important.

AME resembles the syndrome observed in subjects ingesting large amounts of liquorice or taking the now redundant antiulcer drug carbenoxolone, both of which contain glycyrrhetinic acid, an inhibitor of type 2 11β-HSD, thus explaining the hypertension and hypokalaemia observed with these compounds. Spillover access of cortisol to the mineralocorticoid receptor may also, at least partly, explain the hypertension accompanying some forms of Cushing’s syndrome and glucocorticoid resistance.

Liddle's syndrome

Liddle described a family in which the siblings were affected by early-onset hypertension and hypokalaemia, but with low renin and aldosterone levels. The clue to the nature of the molecular defect underlying this autosomal dominant disorder came from the observation that the hypertension does not respond to spironolactone, the mineralocorticoid receptor antagonist, but does respond to direct inhibitors (such as triamterene or amiloride) of the epithelial sodium channel, which mediates the effects of activation of the mineralocorticoid receptor. This indicated that the defect lay downstream of the mineralocorticoid receptor, with subsequent work revealing activating mutations in genes (SCNN1B, SCNN1G) encoding the β- or γ-subunits of the trimeric epithelial sodium channel, which is located in the distal nephron and represents the final effector molecule of the renin–angiotensin–aldosterone system in the kidney. All mutations so far identified cause an alteration or deletion of a proline-rich (PY) motif in the C-terminal cytoplasmic tails of the subunits that is necessary for regulatory proteins such as Nedd4 to bind and internalize the channel. When this is impaired the channel remains constitutively active at the cell surface, leading to over-reabsorption of sodium and water.

Pseudohypoaldosteronism type 2 (Gordon’s syndrome)

Pseudohypoaldosteronism type 2 (PHA2), also known as Gordon’s syndrome, is an autosomal dominant disorder that causes elevated blood pressure accompanied by hyperkalaemia, despite normal renal glomerular filtration. Mild hyperchloraemia, metabolic acidosis, and suppressed plasma renin activity are variable associated findings. Hypercalciuria can also be a feature, leading to osteopenia, osteoporosis, and kidney stone disease. The hypertension and physiological abnormalities are corrected by thiazide diuretics.

Recent studies have established that at least some cases of PHA2 are due to mutations in two members, WNK1 and WNK4, of the WNK (With No K, K = lysine) family of serine-threonine kinases. Both proteins localize to the distal nephron, where they contribute to regulation of the salt reabsorption by the Na-Cl cotransporter (SLC12A3) and the linked process of potassium secretion by the renal outer medullary potassium channel (ROMK). WNK4 is a negative regulator of both channels. PHA2-causing mutations in WNK4 result in loss of its inhibition of the Na-Cl cotransporter but at the same maintain or increase its ability to inhibit potassium secretion via ROMK, providing an explanation for why the hypertension caused by WNK4 mutations is accompanied by hyperkalaemia. Current evidence suggests that WNK1 acts as a negative regulator of WNK4: PHA2-causing mutations in WNK1 are associated with increased expression of the protein and hence are expected to relieve WNK4- mediated suppression of the Na-Cl cotransporter. The Na-Cl transporter is the target for thiazide diuretics, which explains the specific clinical response of PHA2 to this class of drugs.

Defects in the Na-Cl cotransporter lead to the salt-losing Gitelman’s syndrome, which as described below is the mirror image of PHA2.

Other monogenetic forms of hypertension

A missense mutation in the ligand-binding domain of the mineralocorticoid receptor has been found to cause an autosomal dominant form of hypertension that is markedly accelerated in pregnancy. The mutation, MR S810L, causes partial, aldosterone-independent activation of the receptor, causing carriers to develop hypertension before age 20. Compounds such as progesterone that normally bind to but do not activate the mineralocorticoid receptor are all potent agonists of the mutant receptor, hence MR S810L carriers have dramatic acceleration of hypertension during pregnancy stimulated by the 100-fold rise in progesterone. Although the MR S810L mutation is extremely rare, the finding does raise the question of whether related mechanisms may underlie other forms of hypertension in pregnancy.

A gene causing autosomal dominant hypertension in conjunction with type E brachydactyly in a large Turkish kindred has been mapped to chromosome 12p. The hypertension in this syndrome, unlike most of the disorders described above, closely resembles essential hypertension with no evidence of volume expansion or electrolyte imbalance. The genetic defect is unknown.

Genetic defects causing hypertension

A number of mendelian syndromes where hypotension is a feature have recently been characterized at the molecular level (Table 1). Many are mirror images of the genetic abnormalities causing the mendelian forms of hypertension described above.

Table 1 Biochemical and therapeutic characteristics of Glucocorticoid remediable aldosteronism (GRA), syndrome of apparent mineralocorticoid excess (AME), Liddle’s syndrome, and Gordon’s syndrome
  GRA AME Liddle’s Gordon’s
Plasma electrolytes ↑Na ↓K ↑Na ↓K ↑Na ↓K ↑Na ↑K
Plasma aldosterone ↑↓
Plasma renin
Specific treatment Dexamethasone Spironolactone Amiloride Thiazide

Note that while the biochemical changes are characteristic, they are not invariably present.

Pseudohypoaldosteronism type 1 (PHA1) occurs in two forms, autosomal recessive and autosomal dominant. Both are characterized by life-threatening dehydration in the neonatal period, hypotension, salt wasting, hyperkalaemia, metabolic acidosis, and marked elevation of renin and aldosterone. The autosomal recessive form is due to inactivating mutations (compare with Liddle’s syndrome) in one of the genes SCNN1A, SCCN1B or SCNN1G, encoding (respectively) the α, β, and γ subunits of the epithelial sodium channel, while the autosomal dominant form is due to loss-of-function mutations in the gene (NR3C2) encoding the mineralocorticoid receptor.

Gitelman’s syndrome is an autosomal recessive disorder characterized by hypotension, neuromuscular abnormalities, hypokalaemia, hypomagnesaemia, hypocalciuria, metabolic alkalosis, and an activated renin–angiotensin system. It arises due to inactivating mutations in the gene encoding the renal thiazide-sensitive Na-Cl cotransporter (SLC12A3), and typically presents in adolescence or early adulthood with neuromuscular signs and symptoms.

Bartter’s syndrome is caused by mutations in one of the genes that encode regulators of chloride transport within the thick ascending limb of nephron. Defects in genes encoding bumetanide-sensitive sodium-(potassium)-chloride co-transporter 2 (SLC12A1), ATP-regulated potassium channel ROM-K (KCNJ1), chloride channel Kb (CLCNKB), and barttin (BSDN) are responsible for four types of Bartter’s syndrome. The manifestation of these autosomal recessive disorders is heterogeneous, but the most typical clinical presentations include early onset (infancy or childhood), hypovolaemia and polyuria, low or normal blood pressure, elevated prostaglandin levels and nephrocalcinosis. The recently identified Bartter-like syndrome occurring in subjects with mutations in the CASR gene (that encodes extracellular basolateral calcium sensing receptor) manifests as hypocalcemic hypercalciuria. For further discussion of Gitelman’s and Bartter’s syndrome, see Chapter 21.2.2.

Does my patients have a recognised form of monogenetic hypertension?

Identification that a patient has GRA, AME, Liddle’s syndrome, or Gordon’s syndrome has important consequences for treatment (Table 1) and family screening. Phenotypic expression is highly variable, but all of the syndromes are extremely rare and suspicion will usually go unrewarded. Features that may suggest a diagnosis of mendelian hypertension include a young age of onset, moderate to severe hypertension, strong family history, consanguinity (for the autosomal recessive disorders), and electrolyte abnormalities, particularly of potassium (although this is not invariable). A good starting point, as described in Chapter 16.17.4, is the measurement of plasma renin activity and plasma aldosterone. If the aldosterone is significantly elevated then the differential diagnosis lies between the various forms of Conn’s syndrome and GRA. Diagnosis of GRA would be supported by the finding of elevated 18-hydroxycortisol and 18-oxocortisol in the urine, and a positive dexamethasone suppression test, suppression of plasma aldosterone levels to less than 4 ng/dl with 0.75 to 2.0 mg/day for at least 2 days being reported to have a greater than 90% specificity and sensitivity for the diagnosis, and GRA can now also be relatively easily confirmed by finding a chimeric gene fragment with DNA testing.

If the aldosterone level is suppressed, then finding an increased ratio of cortisol/cortisone metabolites in the urine would support a diagnosis of AME. The presence of hyperkalaemia, hyperchloraemia and metabolic acidosis would suggest a diagnosis of Gordon’s syndrome. No biochemical abnormalities specifically support a diagnosis of Liddle’s syndrome. Ultimately, diagnosis of AME, Liddle’s syndrome, and Gordon’s syndrome also requires DNA confirmation, but this is not as straightforward as it is with GRA since several different mutations can give rise to each syndrome.

Further reading

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Geller DS, et al. (2000). Activating mineralocorticoid receptor mutation in hypertension exacerbated by pregnancy. Science, 289, 119–23.

Lifton RP, et al. (1992). A chimaeric 11 ß-hydroxylase/aldosterone synthase gene causes glucocorticoid-remediable aldosteronism and human hypertension. Nature, 355, 262–65.

Lifton RP, et al. (2001). Molecular mechanisms of human hypertension. Cell, 104, 545–56.
 
Mune T, et al. (1995). Human hypertension caused by mutations in the kidney isozyme of 11β-hydroxysteroid dehydrogenase. Nat Genet, 10, 394–9.
 
Shimkets RA, et al. (1994). Liddle’s syndrome: Heritable human hypertension caused by mutations in the β subunit of the epithelial sodium channel. Cell, 79, 407–14.
 
Wilson FH, et al. (2001). Human hypertension caused by mutations in WNK kinases. Science, 293, 1107–12.